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The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A, TET2, and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p < 0.0001), lower RFS (HR = 3.36, p < 0.0001) and OS (HR = 3.81, p = 0.00023) whereas persistence of only one mutation was not. In 100 analyzable patients, WT1-MRD, but not NGS-MRD, was an independent factor for RFS and OS. In the subset of 67 NPM1 mutated patients, both NPM1 mutation detection (p = 0.0059) and NGS-MRD (p = 0.035) status were associated with CIR. We conclude that detectable NGS-MRD including DTA mutations correlates with unfavorable prognosis in AML. Its integration with alternative MRD strategies in AML management warrants further investigations.
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Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda , Mutação , Neoplasia Residual , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Adulto Jovem , Prognóstico , DNA Metiltransferase 3A , Idoso de 80 Anos ou mais , DNA (Citosina-5-)-Metiltransferases/genética , Adolescente , Proteínas Repressoras/genética , Análise Mutacional de DNARESUMO
Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.
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Classe Ib de Fosfatidilinositol 3-Quinase , Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Humanos , Animais , Camundongos , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Proteólise/efeitos dos fármacos , Feminino , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêuticoRESUMO
Recent advancements in shRNA and Cas protein technologies have enabled functional screening methods targeting genes or non-coding regions using single or pooled shRNA and sgRNA. CRISPR-based systems have also been developed for modulating DNA accessibility, resulting in CRISPR-mediated interference (CRISPRi) or activation (CRISPRa) of targeted genes or genomic DNA elements. However, there is still a lack of software tools for integrating diverse array of functional genomics screening outputs that could offer a cohesive framework for comprehensive data integration. Here, we developed PitViper, a flexible and interactive open-source software designed to fill this gap, providing reliable results for the type of elements being screened. It is an end-to-end automated and reproducible bioinformatics pipeline integrating gold-standard methods for functional screening analysis. Our sensitivity analyses demonstrate that PitViper is a useful tool for identifying potential super-enhancer liabilities in a leukemia cell line through genome-wide CRISPRi-based screening. It offers a robust, flexible, and interactive solution for integrating data analysis and reanalysis from functional screening methods, making it a valuable resource for researchers in the field.
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ABSTRACT: Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease presenting with either myeloproliferative or myelodysplastic features. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative option, but the inherent toxicity of this procedure makes the decision to proceed to allo-HCT challenging, particularly because patients with CMML are mostly older and comorbid. Therefore, the decision between a nonintensive treatment approach and allo-HCT represents a delicate balance, especially because prospective randomized studies are lacking and retrospective data in the literature are conflicting. International consensus on the selection of patients and the ideal timing of allo-HCT, specifically in CMML, could not be reached in international recommendations published 6 years ago. Since then, new, CMML-specific data have been published. The European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee assembled a panel of experts in the field to provide the first best practice recommendations on the role of allo-HCT specifically in CMML. Recommendations were based on the results of an international survey, a comprehensive review of the literature, and expert opinions on the subject, after structured discussion and circulation of recommendations. Algorithms for patient selection, timing of allo-HCT during the course of the disease, pretransplant strategies, allo-HCT modality, as well as posttransplant management for patients with CMML were outlined. The keynote message is, that once a patient has been identified as a transplant candidate, upfront transplantation without prior disease-modifying treatment is preferred to maximize chances of reaching allo-HCT whenever possible, irrespective of bone marrow blast counts.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Crônica , Transplante Homólogo , Adulto , Humanos , Gerenciamento Clínico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mielomonocítica Crônica/terapia , Sociedades Médicas/normasAssuntos
Anticorpos Biespecíficos , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Indução de Remissão , Humanos , Anticorpos Biespecíficos/uso terapêutico , Adulto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Quimioterapia de Consolidação , Resultado do Tratamento , IdosoRESUMO
Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype-tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double-strand breaks, as shown by increased levels of phosphorylate histone H2AXγ (p-H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin-dependent kinase 1 (CDK1)-cyclin B1 and M-phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells.
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Apoptose , Ciclo Celular , Leucemia Mieloide Aguda , Monócitos , Molécula 2 de Interação Estromal , Humanos , Apoptose/genética , Monócitos/metabolismo , Monócitos/patologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Molécula 2 de Interação Estromal/metabolismo , Molécula 2 de Interação Estromal/genética , Ciclo Celular/genética , Proliferação de Células , Linhagem Celular Tumoral , Diferenciação Celular , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Feminino , MasculinoRESUMO
Drug combinations have been of increasing interest in recent years for the treatment of complex diseases such as cancer, as they could reduce the risk of drug resistance. Moreover, in oncology, combining drugs may allow tackling tumor heterogeneity. Identifying potent combinations can be an arduous task since exploring the full dose-response matrix of candidate combinations over a large number of drugs is costly and sometimes unfeasible, as the quantity of available biological material is limited and may vary across patients. Our objective was to develop a rank-based screening approach for drug combinations in the setting of limited biological resources. A hierarchical Bayesian 4-parameter log-logistic (4PLL) model was used to estimate dose-response curves of dose-candidate combinations based on a parsimonious experimental design. We computed various activity ranking metrics, such as the area under the dose-response curve and Bliss synergy score, and we used the posterior distributions of ranks and the surface under the cumulative ranking curve to obtain a comprehensive final ranking of combinations. Based on simulations, our proposed method achieved good operating characteristics to identifying the most promising treatments in various scenarios with limited sample sizes and interpatient variability. We illustrate the proposed approach on real data from a combination screening experiment in acute myeloid leukemia.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Teorema de Bayes , Combinação de Medicamentos , Projetos de Pesquisa , Tamanho da Amostra , Neoplasias/tratamento farmacológico , Relação Dose-Resposta a DrogaRESUMO
Genetic testing has been applied for decades in clinical routine diagnostics of hematological malignancies to improve disease (sub)classification, prognostication, patient management, and survival. In recent classifications of hematological malignancies, disease subtypes are defined by key recurrent genetic alterations detected by conventional methods (i.e., cytogenetics, fluorescence in situ hybridization, and targeted sequencing). Hematological malignancies were also one of the first disease areas in which targeted therapies were introduced, the prime example being BCR::ABL1 inhibitors, followed by an increasing number of targeted inhibitors hitting the Achilles' heel of each disease, resulting in a clear patient benefit. Owing to the technical advances in high-throughput sequencing, we can now apply broad genomic tests, including comprehensive gene panels or whole-genome and whole-transcriptome sequencing, to identify clinically important diagnostic, prognostic, and predictive markers. In this review, we give examples of how precision diagnostics has been implemented to guide treatment selection and improve survival in myeloid (myelodysplastic syndromes and acute myeloid leukemia) and lymphoid malignancies (acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia). We discuss the relevance and potential of monitoring measurable residual disease using ultra-sensitive techniques to assess therapy response and detect early relapses. Finally, we bring up the promising avenue of functional precision medicine, combining ex vivo drug screening with various omics technologies, to provide novel treatment options for patients with advanced disease. Although we are only in the beginning of the field of precision hematology, we foresee rapid development with new types of diagnostics and treatment strategies becoming available to the benefit of our patients.
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Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Leucemia Mieloide Aguda , Humanos , Medicina de Precisão , Hibridização in Situ Fluorescente , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Leucemia Mieloide Aguda/terapiaRESUMO
Whether the LSC17 gene expression can improve risk stratification in the context of next generation sequencing-based risk stratification and measurable residual disease (MRD) in patients with intensively treated AML has not been explored. We analyzed LSC17 in 504 adult patients prospectively treated in the ALFA-0702 trial. RUNX1 or TP53 mutations were associated with higher LSC1 scores while CEBPA and NPM1 mutations were associated with lower scores. Patients with high LSC17 scores had a lower rate of complete response (CR) in a multivariable analysis (odds ratio, 0.41; P = .0007), accounting for European LeukemiaNet 2022 (ELN22), age, and white blood cell count (WBC). LSC17-high status was associated with shorter overall survival (OS) (3-year OS: 70.0% vs 52.7% in patients with LSC17-low status; P < .0001). In a multivariable analysis considering ELN22, age, and WBC, patients with LSC17-high status had shorter disease-free survival (DFS) (hazard ratio [HR], 1.36; P = .048) than those with LSC17-low status. In 123 patients with NPM1-mutated AML in CR, LSC17-high status predicted poorer DFS (HR, 2.34; P = .01), independent of age, WBC, ELN22 risk, and NPM1-MRD. LSC-low status and negative NPM1-MRD identified a subset comprising 48% of patients with mutated NPM1 with a 3-year OS from CR of 93.1% compared with 60.7% in those with LSC17-high status and/or positive NPM1-MRD (P = .0001). Overall, LSC17 assessment refines genetic risk stratification in adult patients with AML treated intensively. Combined with MRD, LSC17 identifies a subset of patients with NPM1-mutated AML with excellent clinical outcome.
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Leucemia Mieloide Aguda , Nucleofosmina , Adulto , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Intervalo Livre de Doença , Fatores de Risco , Neoplasia Residual/genéticaRESUMO
Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18-60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4-78.5%) and 57.1% (95%CI: 39.5-82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.
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Leucemia Mieloide Aguda , Adulto , Criança , Humanos , Intervalo Livre de Doença , Tirosina Quinase 3 Semelhante a fms/genética , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Indução de RemissãoRESUMO
Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P<0.001). It was negligible in patients older than 70 years reflecting our own transplant policy but also barriers to transplantation (comorbidities and remission status). However, HSCT patients need to survive, be considered eligible both by the referring and the HSCT physicians and have a suitable donor to get transplantation. We, thus, comprehensively analyzed the complete decision-making and outcome of all our AML patients from diagnosis to last followup to decipher how patient allocation and therapy inform the value of HSCT. The role of HSCT in AML is shifting with broad access to different donors including haploidentical ones. Thus, it may (or may not) lead to increased numbers of allogeneic HSCT in AML in adults.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Idoso , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Transplante Homólogo , Leucemia Mieloide Aguda/terapia , Indução de Remissão , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
Hyperleukocytosis is associated with a significant early mortality rate in patients with acute myeloid leukemia (AML). To date, no controlled trial has ever evaluated a strategy to reduce this risk, and the initial management of these patients remains heterogeneous worldwide. The aim of the present study was to evaluate the influence of a short course of intravenous dexamethasone on the early outcomes of patients with hyperleukocytic AML with white blood cell (WBC) count above 50 × 109/L. Clinical and biological data of all consecutive patients (1997-2017) eligible for intensive chemotherapy from a single center were retrospectively collected. A total of 251 patients with a median age of 51 years and a median WBC count of 120 × 109/L were included, 95 of whom received dexamethasone. Patients treated with dexamethasone had higher WBC count and a more severe disease compared with those who did not, and they presented more often with leukostasis and hypoxemia, resulting in a more frequent need for life-sustaining therapies (p < 0.001). To account for these imbalances, patients were compared after adjusting for a propensity score, which included all variables with a prognostic influence in the overall cohort. In the matched cohort, dexamethasone was associated with lower early death (OR = 0.34, p = 0.0026) and induction failure rate (OR = 0.44, p = 0.02) and better overall survival (HR = 0.60, p = 0.011), with no impact on relapse risk (cHR = 0.73, p = 0.39). The overall survival benefit was confirmed among all tested subgroups. This study suggests that dexamethasone administration is safe and associated with a lower risk of induction mortality in patients with hyperleukocytic AML and deserves prospective evaluation.
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Leucemia Mieloide Aguda , Leucocitose , Humanos , Pessoa de Meia-Idade , Leucocitose/tratamento farmacológico , Pontuação de Propensão , Estudos Retrospectivos , Leucemia Mieloide Aguda/terapia , Dexametasona/uso terapêuticoRESUMO
Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18-84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis. SIGNIFICANCE: We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL. See related commentary by Saiki and Ogawa, p. 102. This article is highlighted in the In This Issue feature, p. 101.
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Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Idoso , Adulto , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Hematopoiese Clonal , Estudos Prospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Mutação , Aneuploidia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
PURPOSE: Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML). PATIENTS AND METHODS: Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m2/d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression. RESULTS: One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 109/L and 31.2 × 109/L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System-mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients (P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm (P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04). CONCLUSION: Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407).
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Leucemia Mielomonocítica Aguda , Leucemia Mielomonocítica Crônica , Humanos , Idoso , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/diagnóstico , Decitabina , Hidroxiureia/efeitos adversos , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Internal tandem duplications in the FLT3 gene, termed FLT3-ITDs, are useful molecular markers in acute myeloid leukemia (AML) for patient risk stratification and follow-up. FLT3-ITDs are increasingly screened through high-throughput sequencing (HTS) raising the need for robust and efficient algorithms. We developed a new algorithm, which performs no alignment and uses little resources, to identify and quantify FLT3-ITDs in HTS data. RESULTS: Our algorithm (FiLT3r) focuses on the k-mers from reads covering FLT3 exons 14 and 15. We show that those k-mers bring enough information to accurately detect, determine the length and quantify FLT3-ITD duplications. We compare the performances of FiLT3r to state-of-the-art alternatives and to fragment analysis, the gold standard method, on a cohort of 185 AML patients sequenced with capture-based HTS. On this dataset FiLT3r is more precise (no false positive nor false negative) than the other software evaluated. We also assess the software on public RNA-Seq data, which confirms the previous results and shows that FiLT3r requires little resources compared to other software. CONCLUSION: FiLT3r is a free software available at https://gitlab.univ-lille.fr/filt3r/filt3r . The repository also contains a Snakefile to reproduce our experiments. We show that FiLT3r detects FLT3-ITDs better than other software while using less memory and time.